Friday, November 25, 2011

gut instinct is depressing

does Immune system has any role besides protecting the body from infections? In my opinion, the answer is probably NO. Once in a while, however, you may find a study claiming otherwise (for example, study claiming that adaptive immune system improves neuron function and memory (1). These type of studies are usually based on observations derived from mice with a defective immune system (missing one or several components of immune system). The main challenge to these type of conclusions is the fact that because normal body harbors myriad varieties of microbes (in the gut, skin, oral cavity, etc.), then even a simple alteration of immune system may indirectly affect other tissue's function though its direct (missing)impact on microbiota. In order to properly address the involvement of immune system in other tissues function experiment should be carried out in the absence of microbiota, for example, in germ-free mice.

If you interested to know more whether immune system could affect other tissue's function and also to illustrate my point, I will recommend reading the following paper that appeared recently in Nature Medicine. This study, by Shulzhenko N and Morgun A et al., looked at intestinal tissue function in the absence of B cells (2). Using several lines of B cell or immunoglobulin (Ig) knock-out (KO) mice and gene microarray analysis, they found that there was very similar changes of intestinal tissue in mice missing B cells or IgA compared to wild type littermates (Fig 2c). In general, genes involved in defense were up-regulated and genes involved in metabolism were down-regulated in B cell KO mice compared to wild type littermates. This may have implied that B cells modulate intestine tissue function. However, to rule out indirect effect of microbiota, they carried out the same experiment in germ-free B cell KO or germ-free wild type mice. As expected, the difference in gene expression of intestinal tissue between B cell KO and wild type mice disappeared on germ-free background (Fig 3c,d). Of note, similar down-regulation of intestinal tissue metabolism occurred in both B cell KO and RAG KO mice (that lacks T cells as well) but it did not occur on germ-free background. These data suggested that improper activation of adaptive immune system in the absence of B cells were not responsible for down-regulation of intestinal metabolism and that microbiota was involved. Because gene expression profile of B cell KO mice was very similar to gene expression profile of intestinal tissue derived from mice with intestinal epithelial-specific deletion of GATA4 transcription factor, the authors concluded that altered microbiota (as a result of lack of B cells/IgA) directly affected intestine tissue metabolism. They also supported this conclusion by profiling gene expression of isolated intestinal epithelial cells from B cell KO mice and using mouse intestinal cell line treated with different inflammatory stimuli. In my opinion, the caveat of this interpretation is the fact that (a) gut tissue contains diverse set of innate immune cells (for example, lymphoid-tissue inducer-like cells) that could have affected gut metabolism and (b) intestinal epithelial cells isolated from B cell KO mice might had already received signals from these innate immune system (and not directly from microbiota) (in Fig. 5c). In my opinion, the better way to support their conclusion would have been to isolate intestinal epithelial cells from germ-free mice and treat them with different microbes or their components.

Overall, this study is one of best example of how proper experimental approach reveals the hidden effect of microbiota on intestinal tissue in the absence of one component of immune system, in this case the absence of B cells (and IgA).